DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Stefania Modafferi, Stefania Farina, Francesca Esposito, Ornella Brandi, Michela Di Salvio, Ilaria Della Valle, Sara D’Uva, Eveljn Scarian, Giada Cicio, Adelaide Riccardi, Federica Pisati, Anna Garbelli, Tiziana Santini, Orietta Pansarasa, Mariangela Morlando, Nadia D’Ambrosi, Mauro Cozzolino, Gianluca Cestra, Fabrizio d’Adda di Fagagna, Ubaldo Gioia, Sofia Francia
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Abstract

Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUSP525L, co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUSP525L CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In Drosophila melanogaster, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS CIs include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.

Abstract Image

TDP-43和突变FUS细胞质包涵体形成诱导的DNA损伤反应缺陷及其药理补救
肌萎缩性侧索硬化症(ALS)患者运动神经元受损的标志是TDP-43和FUS胞质包涵体(CIs)的形成以及DNA损伤的积累。然而,在这种病理中,CIs对DNA损伤反应(DDR)和修复的影响仍未得到探讨。在这里,我们发现TDP-43和FUSP525L的CIs与应激颗粒共定位,导致与物理DNA断裂相关的DDR激活功能失调。抑制DDR激酶ATM的活性,而不抑制ATR的活性,可以消除DDR信号,这表明DNA双链断裂(DSBs)是DDR激活的主要来源。此外,具有TDP-43和FUSP525L CIs的细胞在dsb处表现出DNA损伤诱导的RNA合成减少。我们之前的研究表明,在小RNA加工过程中,两种核糖核酸内切酶DROSHA和DICER也与TDP-43和FUS相互作用,有助于dsb的DDR信号传导。依诺沙星通过提高DICER的酶活性来刺激DDR和修复,在培养的CIs细胞和ALS小鼠模型中恢复了熟练的DDR,减少了DNA损伤的积累。在黑腹果蝇中,Dicer-2过表达可挽救tdp -43介导的视网膜变性。总之,我们的研究结果表明,TDP-43和FUS CIs引起的有害影响包括基因毒性应激,而DNA损伤信号传导和修复的药理刺激抵消了它。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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